XIAP deficiency (XLP2)

Doctors may suspect XIAP deficiency in a boy or man with HLH that keeps coming back, or a swollen spleen that returns with fevers and low blood counts. Crohn’s-like bowel disease that starts early in life, is severe or does not respond to usual treatment is another clue.

A lab test called flow cytometry can show whether blood cells make the XIAP protein. A second test checks how well XIAP works. It measures how white blood cells called monocytes respond to a molecule based on part of a bacterium. Very high blood levels of an inflammatory signal called IL-18 can also be a clue. But some gene changes leave a protein that is present yet does not work, so these tests can miss the condition. A gene test of XIAP (also called BIRC4) is what confirms the diagnosis.

Diagnosis can take time. In a 2021 study of 40 patients who later had transplants, the median age at first symptoms was about 3 years, but the median age at diagnosis was 5.5 years. Once the family’s gene change is known, brothers and other male relatives can be tested. Female relatives can learn if they are carriers, and testing during pregnancy is possible.

Care depends on the problem. HLH can be treated with the HLH-94 or HLH-2004 approach, which uses steroids and the chemotherapy medicine etoposide. Some experts find that steroids alone often control it. Rituximab, a medicine that removes B cells, may be used when EBV drives HLH.

Bowel disease is first treated with usual inflammatory bowel disease medicines, such as steroids, azathioprine or anti-TNF drugs. It often does not respond well, and surgery is sometimes needed.

A donor stem cell transplant is the only known cure. It is usually considered for severe disease, such as HLH or bowel disease that does not respond to treatment. Early transplants that used full-strength conditioning went badly. Common causes of death were bleeding in the lungs and a serious liver problem called veno-occlusive disease. Gentler reduced-intensity conditioning has improved survival, especially when HLH is under control first. Bowel disease has cleared completely after transplant in some people, but it can take a long time.

Graft-versus-host disease is a particular danger. In an international study of 40 patients, those who developed moderate to severe acute graft-versus-host disease, or who had a mismatched donor, were far less likely to survive. HLH can also flare again after transplant. One series reported this in up to half of patients, while the 40-patient study saw possible early flares in 3. Gene therapy is being studied in the laboratory and is not an approved option.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

The course of XIAP deficiency varies a great deal. Some boys have repeated HLH or severe bowel disease from early childhood. Others stay well into adulthood. HLH and severe bowel disease are the main dangers.

HLH tends to be milder and less often fatal in XIAP deficiency than in XLP1, though it often comes back. Severe bowel disease is a serious risk, mostly because of bleeding in the gut. When a transplant is needed, results have improved with gentler (reduced-intensity) conditioning. Having HLH under control before transplant and having a well-matched donor are both linked to better survival.

European transplant guidelines from 2021 describe transplant results in XIAP deficiency as worse than in other inherited forms of HLH. A 2021 study of 40 patients given gentler conditioning found two-year survival similar to other genetic forms of HLH. Most figures come from small groups of patients, so they describe groups, not any one person.